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Relationship: 908

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

N/A, Mitochondrial dysfunction 1 leads to Degeneration of dopaminergic neurons of the nigrostriatal pathway

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits non-adjacent Moderate Low Cataia Ives (send email) Open for citation & comment TFHA/WNT Endorsed

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

Neurons are characterized by the presence of neurites, the formation of action potentials, and the release and re-uptake of neurotransmitters into the synaptic cleft. The presence of long extensions implies a significant enlargement of total cell surface. In combination with the transmission of action potentials that require a continuous maintenance of active transport processes across the membrane, the steady state energy demand of these neurons is significantly higher compared with non-neuronal cells. Dopaminergic (DA) neurons located in the substantia nigra pars compacta (SNpc) that project into the striatum are unique with respect of the total length of their neurites and the number of synapses that are significantly higher compared with other neuronal cell types (Bolam et al., 2012). Besides this complex morphology DA neurons have a distinctive physiological phenotype that could contribute to their vulnerability (Surmeier et al., 2010). Other features such as high energy demand, high calcium flux, dopamine autoxidation process as well as high content of iron and high content of microglia makes these DA neurons at vulnerable population of cells to oxidative stress produced by mitochondrial dysfunction. These architectural features of SNpc DA neurons render this cell type as particularly vulnerable to impairments in energy supply. Mitochondrial dysfunction, either evoked by environmental toxins such as the complex I inhibitor rotenone or MPTP, by oxidative modifications of components of the mitochondrial respiratory chain, or by genetic impairments of mitochondrial ATP generation hence have direct influence on the function and integrity of SNpc DA neurons.

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

Mitochondria are organelles essentials for multiple cellular processes, including production of ATP, maintenance of calcium homeostasis, management of ROS production and apoptosis. Mitochondrial dynamics are also critical for the maintenance of cellular homeostasis, which involve multiple factors controlling mitophagy (Youle et al. 2012). Deregulation of mitochondrial functions may impact any neuronal population; however, SNpc DA neurons are indeed the most vulnerable population in PD. Multiple factors are related to their vulnerability: These include autonomous activity, broad action potentials, low intrinsic calcium buffering capacity, poorly myelinated long highly branched axons and terminal fields, and use of a catecholamine neurotransmitter, often with the catecholamine-derived neuromelanin pigment (Sulzer et al. 2013; Surmeier et al.2010).

The above mentioned factors imply a significantly higher total cell surface and a high energy requirement in order to maintain the re-distribution of ions across the membrane following an action potential. In addition, SNpc DA neurons are characterized by significantly higher numbers of synapses compared with other neuronal types or with DA neurons of different anatomical localizations (Anden et al., 1966; Kawaguchi et al., 1990; Kita et al., 1994; Bevan et al., 1998; Wu et al., 2000; Tepper et al., 2004). In humans, ca. 10 times higher numbers of synapses compared with rats are expected, making human DA neurons particularly vulnerable (Bolam et al., 2012; Matsuda et al., 2009). These extreme bioenergetics demands pose SNpc DA neurons energetically “on the edge”. Any stressor that might perturb energy production would hence lead to conditions under which the energy demand would exceed energy supply, resulting in cell damage and ultimately to cell death.

The mechanistic link between mitochondrial dysfunction and loss of SNpc DA neurons also comes from evidence of mutated proteins related to mitochondrial function in familial PD, resulting in reduced calcium capacity, increased ROS production, increase in mitochondrial membrane permeabilization and increase in cell vulnerability (Koopman et al. 2012; Gandhi et al. 2009). In addition, excessive ROS production can damage mitochondrial DNA and activate the intrinsic pathway of apoptosis (Tait et al. 2010). Additional sources of oxidative stress come from the autoxidation of dopamine and the active generation of ROS by activated glia cells; furthermore, the mitochondrial respiratory chain itself represents a source of constant superoxide formation, even under normal conditions (Moosmann et al., 2002).

Imbalance of mitochondrial dynamics have been also reported in a wide range of experimental models of PD and inhibition of the mitochondrial fission proteins (i.e. Drp1) promote mitochondrial fusion and fission and enhanced the release of dopamine from the nigrostriatal terminals (Tieu et al. 2014).

Additional link between mitochondrial dysfunction and the degeneration of DA neurons of the nigrostriatal pathway comes from studies indicating a reduced activity of mitochondrial complex I in human idiopathic PD cases in the substantia nigra (Keeney et al., 2006; Parker et al., 1989, 2008; Swerdlow et al., 1996). The impairment in complex I activity was directly correlated with an elevated sensitivity of SNpc DA neurons and their demise. Transfer of mitochondria from human platelets collected from idiopathic PD subjects into fibroblasts or neuronal cells resulted in elevated levels of basal oxidative stress, a declined supply with ATP, and an elevated vulnerability towards exogenous stressors such as the complex I inhibitors rotenone or the redox cycler paraquat (Swerdlow et al., 1996; Gu et al., 1998). Systemic application of complex I inhibitors such as rotenone or MPTP lead to a preferential loss of nigrostriatal DA neurons, while other brain areas or peripheral cells are not affected to the same degree (Langston et al., 1983).

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

- Several in vitro studies applying rotenone to evoke mitochondrial dysfunction came to the conclusion that rotenone-dependent ROS formation, and not the rotenone-evoked drop in ATP is the primary cause for cell degeneration. These observations are largely based on experimental systems employing the rotenone insensitive NADH dehydrogenase NDI 1. Expression of NDI 1 protected rotenone exposed cells from degeneration. The presence of NDI 1 however results in a substitution of ATP. Endogenously expressed complex I is still present in these models and it can be assumed that rotenone exposure would still lead to a complex I-dependent formation of ROS that precludes the modeling of a precise cause-consequence relationship between either ATP depletion or elevated ROS levels with the demise of DA neurons.

- Several studies indicate a dominant role of ROS in the degeneration of DA neurons, based on models in which rotenone/MPP+ mediated mitochondrial dysfunction and cell degeneration was protected by the presence of exogenously added antioxidants. Maintenance of the endogenous redox potential however is a highly ATP-dependent process. Clear-cut separations between the respective contribution of ROS or the role of an inhibited mitochondrial ATP synthesis on the degeneration of DA neurons is hence difficult to postulate.

- Studies with chronic partial GSH depletions indicated that an experimental reduction of GSH/GSSG by ca. 50 % has no influence on cell viability. Reports involving rotenone and MPP+ however regularly observe degeneration of DA neurons under conditions of GSH depletion around 50 %. These observations indicate a more prominent role of the intracellular drop of ATP evoked by the complex I inhibitors in the process of cell degeneration.

- Studies in which oxidative stress is generated e.g. by the application of DA or 6-OHDA not only observed a challenge of the cellular redox potential, but also reversible and irreversible inhibitory mechanisms of mitochondrial respiratory chain complexes (nitration, S-nitrosation) that are accompanied by an inhibition of the respiratory chain in the absence of pharmacological complex I inhibitors. These observations illustrate the close mutual interaction between oxidative stress and the inhibition of mitochondrial respiration and point to a profound role of direct mitochondrial inhibition also under oxidative stress conditions.

- Mitochondrial dysfunction is generally associated with conditions of oxidative stress. Dysfunctional mitochondria can act as potent source of superoxide. Oxidative stress associated with PD however not only originates from mitochondrial ROS, but also from DA autoxidation and the Fenton reaction, as well as from inflammatory activated adjacent glia. Interpretations on the role of oxidative stress in DA neurons and its role in DA neurodegeneration is hence hampered by the fact that the respective origin of the reactive oxygen species formed (mitochondria, DA autoxidation, inflammation of glia cells) is rather difficult to identify and often shows overlappings (Murphy et al., 2009; Starkov et al., 2008, Cebrian et al., 2015).

- In PD patients, a reduction in complex I activity in the SNpc, but also in peripheral tissue and cells such as platelets, was reported. Studies with isolated mitochondria indicated that for efficient inhibition of mitochondrial ATP formation, an inhibition of complex I by ca. 70 % is necessary (Davey et al., 1996). Reports on the reduction of complex I activity in PD patients however repeatedly indicated an inhibition of only 25-30 % (Schapira et al., 1989; Schapira et al., 1990; Janetzky et al., 1994).

- Data available on the respective inhibition of the components of the respiratory chain are highly dependent on the experimental setup used. Analysis of mitochondrial respiratory chain complex activities in mitochondrial homogenates provide results different from data obtained with intact, isolated mitochondria. These aspects need to be considered in the interpretation of such data (Mann et al., 1992; Parker et al., 2008; Mizuno et al., 1989; Schapira et al., 1990; Cardellach et al., 1993)

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

There are no sex or age restiction for the applicability of this KEr and mitochondrial are essential for most of eukariotyc cells. Rotenone and MPTp have been tested successfully in primates and mice. The mouse C57BL/6 strain is the most frequently used strain in the reported experiments. A difference in vulnerability was observed, particularly for rats, depending on the strain and route of administration. The Lewis strain gives more consistency in terms of sensitivity when compared to the Sprague Dawley. In addition to rodents, the pesticide rotenone has been also studied in Caenorhabditis elegans (C.elegans), Drosophila, zebrafish and Lymnaea Stagnalis (L.stagnalis) (Johnson et al., 2015), indicating that the system is preseved across species.

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Alam MSchmidt WJ.Behav Brain Res. Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. 2002 Oct 17;136(1):317-24.

Andén NE, Hfuxe K, Hamberger B, Hökfelt T (1966) A quantitative study on the nigro-neostriatal dopamine neuron system in the rat. Acta Physiol Scand. 67(3):306-12.

Antunes F, Han D, Rettori D, Cadenas E. (2002) Mitochondrial damage by nitric oxide is potentiated by dopamine in PC12 cells. Biochim Biophys Acta. 1556(2-3):233-8.

Beal MF, Matthews RT, Tieleman A, Shults CW (1998) Coenzyme Q10 attenuates the 1-methyl-4-phenyl-1,2,3,tetrahydropyridine (MPTP) induced loss of striatal dopamine and dopaminergic axons in aged mice. Brain Res. 783(1):109-14.

Berthet A, Margolis EB, Zhang J, Hsieh I, Zhang J, Hnasko TS, Ahmad J, Edwards RH, Sesaki H, Huang EJ, Nakamura K. (2014) Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons. J Neurosci. 34(43):14304-17.

Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci. 3(12):1301-6.

Bevan MD, Booth PA, Eaton SA, Bolam JP (1998) Selective innervation of neostriatal interneurons by a subclass of neuron in the globus pallidus of the rat. J Neurosci. 18(22):9438-52.

Bezard EGross CEFournier MCDovero SBloch BJaber M Exp Neurol. Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter.1999 Feb;155(2):268-73.

Bolam JP, Pissadaki EK (2012) Living on the edge with too many mouths to feed: why dopamine neurons die. Mov Disord. 27(12):1478-83. Cardellach F, Martí MJ, Fernández-Solá J, Marín C, Hoek JB, Tolosa E, Urbano-Márquez A. (1993) Mitochondrial respiratory chain activity in skeletal muscle from patients with Parkinson's disease. Neurology. 43(11):2258-62.

Cebrián C, Loike JD, Sulzer D. (2015) Neuroinflammation in Parkinson's disease animal models: a cell stress response or a step in neurodegeneration? Curr Top Behav Neurosci. 22:237-70.

Chen Y, Zhang DQ, Liao Z, Wang B, Gong S, Wang C, Zhang MZ, Wang GH, Cai H, Liao FF, Xu JP (2015) Anti-oxidant polydatin (piceid) protects against substantia nigral motor degeneration in multiple rodent models of Parkinson's disease. Mol Neurodegener. 10:4. doi: 10.1186/1750-1326-10-4.

Chinta SJ, Andersen JK (2006) Reversible inhibition of mitochondrial complex I activity following chronic dopaminergic glutathione depletion in vitro: implications for Parkinson's disease. Free Radic Biol Med. 41(9):1442-8.

Chiu CC, Yeh TH, Lai SC, Wu-Chou YH, Chen CH, Mochly-Rosen D, Huang YC, Chen YJ, Chen CL, Chang YM, Wang HL, Lu CS (2015) Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism. Exp Neurol. 263:244-53.

Choi BS, Kim H, Lee HJ, Sapkota K, Park SE, Kim S, Kim SJ (2014) Celastrol from 'Thunder God Vine' protects SH-SY5Y cells through the preservation of mitochondrial function and inhibition of p38 MAPK in a rotenone model of Parkinson's disease. Neurochem Res. 39(1):84-96.

Davey GP, Clark JB. (1996) Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria. J Neurochem. 66(4):1617-24.

Du T, Li L, Song N, Xie J, Jiang H (2010) Rosmarinic acid antagonized 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in MES23.5 dopaminergic cells. Int J Toxicol. 29(6):625-33.

Ekstrand M, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, Thams S, Bergstrand A, Hansson FS, Trifunovic A, Hoffer B, Cullheim S, Mohammed AH, Olson L, Larsson NG. (2007) Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A. 104(4):1325-30.

Gandhi S, Wood-Kaczmar A, Yao Z, et al. PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Molecular Cell. 2009;33:627–638.

Giovanni A, P K Sonsalla and R E Heikkila. Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 2: Central administration of 1-methyl-4-phenylpyridinium.Journal of Pharmacology and Experimental Therapeutics September 1994, 270 (3) 1008-1014;

Gu M, Cooper JM, Taanman JW, Schapira AH (1998) Mitochondrial DNA transmission of the mitochondrial defect in Parkinson's disease. Ann Neurol. 44(2):177-86.

Hajieva P, Mocko JB, Moosmann B, Behl C (2009) Novel imine antioxidants at low nanomolar concentrations protect dopaminergic cells from oxidative neurotoxicity. J Neurochem. 110(1):118-32.

Höglinger GU, Féger J, Prigent A, Michel PP, Parain K, Champy P, Ruberg M, Oertel WH, Hirsch EC (2003) Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats. J Neurochem. 84(3):491-502.

Inden MKitamura YTakeuchi HYanagida TTakata KKobayashi YTaniguchi TYoshimoto KKaneko MOkuma YTaira TAriga HShimohama S. Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone. J Neurochem. 2007 Jun;101(6):1491-1504.

Jain A, Mårtensson J, Stole E, Auld PA, Meister A (1991) Glutathione deficiency leads to mitochondrial damage in brain. Proc Natl Acad Sci U S A. 88(5):1913-7.

Jana S, Sinha M, Chanda D, Roy T, Banerjee K, Munshi S, Patro BS, Chakrabarti S (2011) Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: Implications in dopamine cytotoxicity and pathogenesis of Parkinson's disease. Biochim Biophys Acta. 1812(6):663-73.

Janetzky B, Hauck S, Youdim MB, Riederer P, Jellinger K, Pantucek F, Zöchling R, Boissl KW, Reichmann H. (1994) Unaltered aconitase activity, but decreased complex I activity in substantia nigra pars compacta of patients with Parkinson's disease. Neurosci Lett. 169(1-2):126-8.

Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, Greenamyre JT, Liu RM, Forman HJ, Andersen JK (2000) Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease. J Biol Chem. 275(34):26096-101. Kawaguchi Y, Wilson CJ, Emson PC (1990) Projection subtypes of rat neostriatal matrix cells revealed by intracellular injection of biocytin. J Neurosci. 10(10):3421-38.

Johnson ME, Bobrovskaya L. 2015. An update on the rotenone models of parkinson’s disease: Their ability to reproduce features of clinical disease and model gene-environment interactions. 946). 101-16.

Keeney PM, Xie J, Capaldi RA, Bennett JP Jr (2006) Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci. 26(19):5256-64.

Khan FH, Sen T, Maiti AK, Jana S, Chatterjee U, Chakrabarti S (2005) Inhibition of rat brain mitochondrial electron transport chain activity by dopamine oxidation products during extended in vitro incubation: implications for Parkinson's disease. Biochim Biophys Acta. 1741(1-2):65-74.

Khan MM, Raza SS, Javed H, Ahmad A, Khan A, Islam F, Safhi MM, Islam F (2012) Rutin protects dopaminergic neurons from oxidative stress in an animal model of Parkinson's disease. Neurotox Res. 22(1):1-15.

Kita H, Kitai ST (1994) The morphology of globus pallidus projection neurons in the rat: an intracellular staining study. Brain Res. 636(2):308-19.

Koopman W, Willems P (2012) Monogenic mitochondrial disorders. New Engl J Med. 22;366(12):1132-41. doi: 10.1056/NEJMra1012478. Langston JW, Ballard PA Jr (1983) Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. N Engl J Med. 309(5):310.

Mann VM, Cooper JM, Krige D, Daniel SE, Schapira AH, Marsden CD (1992) Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease. 115 ( Pt 2):333-42.

Marella M, Seo BB, Nakamaru-Ogiso E, Greenamyre JT, Matsuno-Yagi A, Yagi T (2008) Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease. PLoS One. 3(1):e1433.

Matsuda W, Furuta T, Nakamura KC, Hioki H, Fujiyama F, Arai R, Kaneko T (2009) Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci. 29(2):444-53.

Matthews RT, Ferrante RJ, Klivenyi P, Yang L, Klein AM, Mueller G, Kaddurah-Daouk R, Beal MF (1999) Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol. 157(1):142-9.

Mizuno Y, Ohta S, Tanaka M, Takamiya S, Suzuki K, Sato T, Oya H, Ozawa T, Kagawa Y. (1989) Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. Biochem Biophys Res Commun. 163(3):1450-5.

Moosmann B, Behl C (2002) Antioxidants as treatment for neurodegenerative disorders. Expert Opin Investig Drugs. 11(10):1407-35. Moussaoui S, Obinu MC, Daniel N, Reibaud M, Blanchard V, Imperato A (2000) The antioxidant ebselen prevents neurotoxicity and clinical symptoms in a primate model of Parkinson's disease. Exp Neurol. 166(2):235-45.

Mudò G, Mäkelä J, Di Liberto V, Tselykh TV, Olivieri M, Piepponen P, Eriksson O, Mälkiä A, Bonomo A, Kairisalo M, Aguirre JA, Korhonen L, Belluardo N, Lindholm D. (2012) Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson's disease. Cell Mol Life Sci. 69(7):1153-65.

Murphy MP. (2009) How mitochondria produce reactive oxygen species. Biochem J. 417(1):1-13.

Muthane URamsay KAJiang HJackson-Lewis VDonaldson DFernando SFerreira MPrzedborski S.Differences in nigral neuron number and sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57/bl and CD-1 mice. Exp Neurol. 1994 Apr;126(2):195-204.

Orimo S, Uchihara T, Kanazawa T, Itoh Y, Wakabayashi K, Kakita A, Takahashi H (2011) Unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve in Parkinson's disease. Neuropathol Appl Neurobiol. 37(7):791-802.

Park SE, Sapkota K, Choi JH, Kim MK, Kim YH, Kim KM, Kim KJ, Oh HN, Kim SJ, Kim S (2014) Rutin from Dendropanax morbifera Leveille protects human dopaminergic cells against rotenone induced cell injury through inhibiting JNK and p38 MAPK signaling. Neurochem Res. 39(4):707-18.

Parker WD Jr, Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol. 26(6):719-23.

Parker WD Jr, Parks JK, Swerdlow RH (2008) Complex I deficiency in Parkinson's disease frontal cortex. Brain Res. 1189:215-8. Perry TL, Godin DV, Hansen S (1982) Parkinson's disease: a disorder due to nigral glutathione deficiency? Neurosci Lett. 1982 Dec 13;33(3):305-10.

Prediger RDRial DMedeiros RFigueiredo CPDoty RLTakahashi RN. Risk is in the air: an intranasal MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) rat model of Parkinson's disease. Ann N Y Acad Sci. 2009 Jul;1170:629-36. doi: 10.1111/j.1749-6632.2009.03885.x.

Prediger RD, Aguiar AS Jr, Matheus FC, Walz R, Antoury L, Raisman-Vozari R, Doty RL.Intranasal administration of neurotoxicants in animals: support for the olfactory vector hypothesis of Parkinson's disease. Neurotox Res. 2012 Jan;21(1):90-116. doi: 10.1007/s12640-011-9281-8. Epub 2011 Oct 15. Review

Rangaraju V, Calloway N, and Ryan TA. 2014. Activity-driven local ATP synthesis is required for synaptic function. Cell. 156(4)825–835.

Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem. 54(3):823-7.

Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson's disease. Lancet. 1(8649):1269.

Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT (2003) Mechanism of toxicity in rotenone models of Parkinson's disease. J Neurosci. 23(34):10756-64.

Sherer TB, Richardson JR, Testa CM, Seo BB, Panov AV, Yagi T, Matsuno-Yagi A, Miller GW, Greenamyre JT (2007) Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson's disease. J Neurochem. 100(6):1469-79.

Snow BJ, Vingerhoets FJ, Langston JW, Tetrud JW, Sossi V, Calne DB. Pattern of dopaminergic loss in the striatum of humans with MPTP induced parkinsonism. J Neurol Neurosurg Psychiatry. 2000 Mar;68(3):313-6.

Starkov AA (2008) The role of mitochondria in reactive oxygen species metabolism and signaling. Ann N Y Acad Sci. 1147:37-52.

Swerdlow RH, Parks JK, Miller SW, Tuttle JB, Trimmer PA, Sheehan JP, Bennett JP Jr, Davis RE, Parker WD Jr (1996) Origin and functional consequences of the complex I defect in Parkinson's disease. Ann Neurol. 40(4):663-71.

Surmeier DJ1, Guzman JN, Sanchez-Padilla J, Goldberg JA. 2010. What causes the death of dopaminergic neurons in Parkinson's disease? Prog Brain Res. 2010;183:59-77. doi: 10.1016/S0079-6123(10)83004-3.

Sulzer D, Surmeier DJ. 2013. Neuronal vulnerability, pathogenesis, and Parkinson’s disease. Movement Disorders. 28 (6) 715-24.

Tait SWG, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010;11:621–632.

Tepper JM, Bolam JP (2004) Functional diversity and specificity of neostriatal interneurons. Curr Opin Neurobiol. 14(6):685-92.

Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan LJ, Ju X, Liu R, Qian H, Marvin MA, Goldberg MS, She H, Mao Z, Simpkins JW, Yang SH (2011) Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem. 286(18):16504-15.

Wu Y, Richard S, Parent A (2000) The organization of the striatal output system: a single-cell juxtacellular labeling study in the rat. Neurosci Res. 38(1):49-62.

Youle RJ, van der Bliek AM. 2012. Mitochondrial fission, fusion and stress. Science. 337:1062–1065.

Zhu C, Vourc'h P, Fernagut PO, Fleming SM, Lacan S, Dicarlo CD, Seaman RL, Chesselet MF (2004) Variable effects of chronic subcutaneous administration of rotenone on striatal histology. J Comp Neurol. 478(4):418-26.